Keywords

1 Case Report

A 40-year-old woman with a history of cutaneous and tendon xanthoma (abnormal accumulation of lipids in macrophages of several tissues) and hypercholesterolemia attended an outpatient clinic of the Kanazawa University Hospital with progressive chest pain lasting for 1 month. The patient was diagnosed with severe hypercholesterolemia (total cholesterol , 800 mg/dL) at 3 years of age by the dermatologist examining her cutaneous xanthoma . The cholesterol biosynthesis inhibitor pravastatin was administered when she was 20 years of age; however, she discontinued the medication because it was ineffective in reducing her cholesterol levels. At an approximately 30 years of age, she experienced chest pain induced by exerting effort or cold atmosphere. Therefore, she restricted her daily activity to minimize chest pain. At 40 years of age, she visited her general physician complaining of progressive chest pain, and she was found to have severe hypercholesterolemia {total cholesterol, 450 mg/dL; normal range < 220 mg/dL, low-density lipoprotein cholesterol (LDL-C), 360 mg/dL; normal range < 140 mg/dL} in laboratory test and ST depression in electrocardiogram, suggesting myocardial ischemia.

The patient was born from a non-consanguinity marriage. Her father was diagnosed with hypercholesterolemia. Her mother died from colon cancer, and no blood cholesterol data was obtained. However, her mother’s elder brother had xanthelasma on his eyelids, suggesting the existence of family history of maternal hypercholesterolemia. The patient’s son and daughter were also diagnosed with hypercholesterolemia; however, their cholesterol levels were milder than that of the proband. She had no coronary risk factors, such as hypertension, impaired glucose tolerance, and smoking habit, other than hypercholesterolemia. She had xanthelasma on her eyelids, xanthoma on her bilateral third and fourth extensor tendons of the hands, tuberculous skin xanthoma on her bilateral elbows, and Achilles tendon xanthomas, which were 18 mm thick (Fig. 5.1). She also had surgical scars from resection of skin xanthoma on her wrists. She had a grade 4/6 late systolic murmur (abnormal sound heard during auscultation of the heart) on the second right sternal border radiating to her neck and bilateral carotid bruits (abnormal sound heard during auscultation of the vessels suggesting its narrowing). A cardiac echocardiography revealed shrinkage of the aortic root and narrowing of the ascending aorta just above the valve (supravalvular aortic stenosis), and Doppler and planimetric analysis suggested severe aortic stenosis (blockage), resulting in a significant pressure gradient. Carotid ultrasonography revealed approximately 50% and 75% stenosis in the right and left common carotid artery, respectively; cardiac catheterization revealed moderate coronary atherosclerosis . Her chest pain resolved successfully following aortic valve replacement surgery.

Fig. 5.1
figure 1

Physical findings of a patient with compound heterozygous familial hypercholesterolemia

The presented case had xanthelasma on her eyelids (top left), tuberculous skin xanthoma on her bilateral elbows (middle left), xanthoma on her bilateral third and fourth extensor tendons of the hands (bottom left), and Achilles tendon xanthoma (18 mm thick in side view of roentgenograph; top and bottom right). The thickness of Achilles tendon on the roentgenograph is to be measured perpendicularly at its thickest part (arrow head)

Full size image

Her serum levels of total cholesterol , LDL-C, and high-density lipoprotein (HDL) cholesterol (normal range; ≥ 40 mg/dL) were 523, 429, and 43 mg/dL, respectively, and her triglyceride level (normal range; < 150 mg/dL) was 122 mg/dL. Her serum level of apolipoprotein B (apoB) (normal range; < 100 mg/dL) was 269 mg/dL. Genetic analysis revealed three mutations in the LDL receptor gene: two (c.904 T > G and c.907C > T) were identified in her father, both of which were changed amino acid sequences. A large deletion in exon 6 of the same gene was found in her maternal family member including uncle. Finally, she was diagnosed with compound heterozygous familial hypercholesterolemia [(FH) HeFH].

She was treated with a low-fat, low-cholesterol, restricted caloric diet and 20 mg daily of rosuvastatin (maximum doses in Japan), a cholesterol biosynthesis inhibitor stronger than old generation statin , such as pravastatin. Her serum levels of LDL-C and apoB reached to 257 mg/dL and 165 mg/dL, respectively. The selective cholesterol absorb inhibitor ezetimibe was also introduced. Following treatment, her LDL-C and apoB levels decreased to approximately 240 and 155 mg/dL, respectively. Because these medicines were only partially effective, LDL-apheresis therapy , which is extracorporeal selective adsorption of apoB-containing lipoproteins, was introduced along with the anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody evolocumab, which inhibits intracellular degradation of LDL receptor. Finally, her serum levels just before LDL-apheresis of LDL-C and apoB reached approximately 170 and 130, respectively. However, even after these intensive cholesterol-lowering therapies, her serum LDL-C levels did not reach to the target level for secondary prevention of coronary artery disease (100 mg/dL): therefore, microsomal triglyceride transfer protein inhibitor is the next treatment option.

2 Diagnosis

2.1 Compound Heterozygous Familial Hypercholesterolemia

Lipids including cholesterol are hydrophobic; thus, they are bound with apolipoproteins to create lipoproteins that circulate in the blood stream. Lipoproteins are composed of a core neutral lipid, mainly cholesteryl ester and triglycerides , surrounded by free cholesterol, phospholipids, and apolipoproteins (Fig. 5.2).

Fig. 5.2
figure 2

Basic structure of lipoprotein

Lipoproteins are composed of a core neutral lipid, mainly cholesteryl ester and triglycerides , surrounded by free cholesterol , phospholipids, and apolipoproteins

Full size image

Cells require cholesterol as an essential material for its membrane. The liver synthesizes bile acid from cholesterol, which is required for uptake lipid from the intestine (exogenous pathway). In some endocrine organs, such as adrenal gland, testis, and ovary, cholesterol is also used as a substrate for steroids, such as testosterone, androsterone, estradiol, and progesterone. Cells can synthesize cholesterol from acetyl-CoA; however, the quantity is not sufficient for the cells, except for hepatocytes. Thus, cholesterol is transported from the liver to the other cells mainly by LDL via the LDL receptor (endogenous pathway). Cholesterol is returned from the peripheral cells including macrophages in atherosclerotic lesion to the liver by HDL (reverse cholesterol transport pathway) (Fig. 5.3).

Fig. 5.3
figure 3

Lipoprotein metabolism

Human lipoprotein metabolism is divided into three categories; the exogenous pathway (chylomicron), the endogenous pathway (mainly LDL), and the reverse cholesterol transport pathway (HDL). LDL receptor, the causal protein of FH, is the main regulator of human cholesterol levels

ABCA1 adenosine triphosphate-binding cassette sub-family A member 1, ABCG1 adenosine triphosphate-binding cassette sub-family G member 1, ABCG5G8 adenosine triphosphate-binding cassette sub-family G member 5/sub-family G member 8, CE cholesteryl ester, CETP cholesteryl ester transfer protein, CHOL cholesterol, FFA free fatty acid, HDL high-density lipoprotein, HTGL hepatic triglyceride lipase, HMG-CoA hydroxymethylglutaryl-CoA, LCAT Lecithin-cholesterol acyltransferase, LDL low-density lipoprotein , LDLR low-density lipoprotein receptor, LPL lipoprotein lipase, MTP microsomal triglyceride transfer protein, NPC1L1 Niemann-Pick C1-like 1, PL phospholipid, SR-BI scavenger receptor class B type 1, TG triglyceride

Full size image

FH is the most severe form of monogenic hypercholesterolemia and is mainly caused by mutations in the LDL receptor gene (Rader et al. 2003, Mabuchi 2017). Endogenous cholesterol is secreted from hepatocytes (liver cells) into circulation as very low-density lipoprotein (VLDL), dilipidated by lipoprotein and hepatic lipases, and consequently metabolized to LDL through intermediate-density lipoprotein (IDL) (Fig. 5.3). LDL is the major transport particle of cholesterol to peripheral cells via the LDL receptor, and the remaining LDL particles in circulation are cleared by the LDL receptor on hepatocytes. LDL particles of FH without functional LDL receptors are congested in circulation because of the inability of the LDL receptor to clear the particles (Fig. 5.3).

FH is a common autosomal dominant hereditary disorder, and there are two forms of FH: individuals with two mutated LDL receptor alleles (homozygous FH: HoFH) and those with a single mutated LDL receptor allele (heterozygous FH: HeFH). The blood total cholesterol levels of HoFH, HeFH with LDL receptor gene mutation, and their normal siblings are trimodal as follows: 713 ± 122, 332 ± 60, and 179 ± 26 mg/dL, respectively (Fig. 5.4) (Mabuchi 2017). Initially, the frequency of HeFH was reported as 1 in 500 general populations; recent advances in genetic analysis have expanded the frequency to 1 in 200–300 general populations (Mabuchi 2017, Nordestgaard et al. 2013). Accordingly, the frequency of HoFH is estimated as 1 in 160,000–360,000 general populations. In certain populations, such as Afrikaners in South Africa, French Canadians, and the Lebanese, the frequency of HeFH is substantially higher than in other regions because of the founder gene effect, whereby these population groups originated from a small number of individuals with a specific LDL receptor gene mutation at a higher frequency than that of the general population.

Fig. 5.4
figure 4

Total cholesterol levels of HoFH, HeFH, and their normal siblings

The blood total cholesterol levels of HoFH, HeFH with LDL receptor gene mutation, and their normal siblings are trimodal as follows: 713 ± 122, 332 ± 60, and 179 ± 26 mg/dL, respectively (Mabuchi 2017)

Full size image

HoFHs cause the development of systemic cutaneous xanthoma and atherosclerosis from childhood; cutaneous xanthomas between the hand fingers and buttocks are specific physical findings for HoFH. Interestingly, as in the case presented here, the manifestation of early atherosclerosis in HoFH is often due to the formation of atheroma along with aortic root, aortic valve, and coronary ostia, which extends to coronary and systemic atherosclerosis thereafter. Supravalvular and aortic valve stenosis can cause acute heart failure or sudden cardiac death (Mabuchi 2017). The development of coronary artery disease (CAD) is decided by the cumulative values of LDL-C levels (Nordestgaard et al. 2013). Thus, HoFH could cause the development of premature CAD before 20 years of age along with extremely high LDL-C levels from the birth if effective cholesterol-lowering therapy is not administered. Thus, early surgical intervention including aortic valve replacement or a Bentall procedure, which is the composite graft replacement of aortic valve, aortic root, and ascending aorta, and coronary artery bypass surgery may be needed. Although it is also important to optimize the other cardiovascular risk factors, such as blood pressure and diabetes , these have minimal impact on the clinical course of HoFH.

HeFHs also initially present as tendon xanthomas in the backs of hands and Achilles’ tendons, and cutaneous tuberculous xanthomas occur during and after the second decade of life. Arcus cornealis and xanthelasma on eyelids are characteristics of FH; however, they are not specific or suitable for the diagnosis of FH. Coronary atherosclerosis detected by coronary computed tomography starts to develop at 23 and 33 years in male and female HeFH patients, respectively (Tada et al. 2015b). Clinically significant CAD usually manifests after 30 years of age for men and 40 years for women.

There are substantial interindividual differences in LDL-C levels among patients with HoFH and HeFH. HoFH is classically divided into two categories: receptor-negative FH with no or minimum LDL receptor activity and receptor-defective FH with substantial residual LDL receptor activity. Although LDL receptor activity can be measured in vitro using skin fibroblasts, it is not routinely performed in clinical practice. The clinical course of receptor-negative FH is usually worse compared with that of receptor-defective FH because of substantially higher cumulative LDL-C levels. Standard medical cholesterol-lowering therapies, which eventually increase hepatic LDL receptor, do not effectively reduce LDL-C levels in patients with receptor-negative HoFH but can substantially reduce LDL-C levels in patients with receptor-defective HoFH.

The diagnosis of HeFH is made by combining elevated LDL-C levels, clinical manifestations (particularly xanthomas) , and family history of hypercholesterolemia and/or premature CAD. Although several different clinical diagnostic criteria of FH have been proposed, the existence of tendon or skin xanthomas, which are the reflection of continuous hypercholesterolemia from birth, is essential for the clinical diagnosis of FH. Of those, the following three diagnostic criteria are major: (a) Simon Broome Register Diagnostic Criteria for FH, (b) Make Early Diagnosis to Prevent Early Death (MedPed) Program Diagnostic Criteria for FH, and (c) Dutch Lipid Clinic Network Diagnostic Criteria for FH (Table 5.1a, 5.1b, and 5.1c). The diagnosis of HoFH is made based on markedly elevated LDL-C levels and a family history of parental HeFH on both sides, except for very rare recessive hereditary conditions.

Table 5.1a Simon Broome Register Diagnostic Criteria for FH
Full size table
Table 5.1b Make Early Diagnosis to Prevent Early Death (MedPed) Program Diagnostic Criteria for FH
Full size table
Table 5.1c Dutch Lipid Clinic Network Diagnostic Criteria for FH
Full size table

A genetic diagnosis is considered to be definitive; however, the annotation of the specific mutation is not always easy. Very recently, comprehensive genetic analysis of known causal genes (LDL receptor, apoB, PCSK9, and LDL receptor adaptor protein 1) has become readily available. Thus, it can be speculated that genetic analysis will play a greater role in future diagnostic criteria of FH. Regarding the patient in the case report, three different mutations in the LDL receptor gene were detected, two (c.904 T > G and c.907C > T) were of a paternal origin and the other (a large deletion in exon 6) was of a maternal origin. Thus, the final diagnosis of the case was compound heterozygous FH, which has a similar significance as HoFH in the clinical setting.

3 Differential Diagnosis

  1. 1.

    Familial defective apolipoprotein B-100 (FDB or FH2)

  2. 2.

    Autosomal dominant hypercholesterolemia due to gain-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (FH3)

  3. 3.

    Autosomal recessive hypercholesterolemia (ARH)

  4. 4.

    Sitosterolemia

  5. 5.

    Secondary hyperlipidemia, such as hypothyroidism

4 Biochemical and Molecular Perspectives

Brown and Goldstein received the Nobel Prize in Physiology or Medicine in 1985 for discovering the mechanisms of receptor-mediated endocytosis and the disruption of the LDL receptor as the cause of FH (Brown and Goldstein 1983). To date, dysfunctions of the LDL receptor pathway are recognized as the causes of FH, including FH2, FH3, and ARH.

The size and densities of the different classes of lipoproteins are determined by their composition; larger lipoproteins are buoyant and have more triglycerides and less apolipoproteins, while smaller lipoproteins are dense and have less triglycerides and more apolipoproteins (Table 5.2). Surface charge revealed by agarose gel electrophoresis varies between lipoproteins according to the amount of charged lipids and the conformations of their apolipoproteins. Hence, lipoproteins can be isolated by numerous techniques including size exclusion chromatography, nuclear magnetic resonance, ultracentrifugation, agarose gel electrophoresis, and polyacrylamide gel electrophoresis. Specific lipoproteins are associated with specific apolipoproteins; however, there is some overlaps (Table 5.2). For example, apoB-100 is associated with all lipoproteins except for chylomicron and HDL, and apoA-I is mainly associated with HDL. LDL is the most abundant lipoproteins in humans.

Table 5.2 Properties of major lipoprotein classes
Full size table

The LDL receptor is a cell surface glycoprotein, which mediates the removal of LDLs and remnant lipoproteins from circulation by binding to apoB and apoE and plays a major role in blood cholesterol level regulation. The extracellular component of the LDL receptor comprises the following domains: a ligand-binding domain; an epidermal growth factor (EGF) precursor homology domain, which contains a six-bladed beta-propeller flanked by cysteine-rich EGF domain; and an O-liked sugar-rich domain (Fig. 5.5) (Gidding et al. 2015). LDL receptors are synthesized in the endoplasmic reticulum (ER) and glycosylated in the Golgi apparatus and then transported to clathrin-coated pits on the cell surface. After LDL binds to the ligand-binding domain on the LDL receptor, the LDL-LDL receptor complex is internalized and delivered to endosomes. In the acidic environment of the endosome, the LDL particle is dissociated from the receptor, which is recycled back to the cell surface, and the particle is degenerated for the storage of intracellular cholesterol (Fig. 5.6).

Fig. 5.5
figure 5

Protein and domains of the LDL receptor

The different domains in LDL receptor protein are encoded by specific regions in the LDL receptor gene

EGF endothelial growth factor

Full size image
Fig. 5.6
figure 6

Regulation of the LDL receptor

Both the LDL receptor and proprotein convertase subtilisin/kexin type 9 (PCSK9) are regulated by sterol regulatory element-binding protein 2 (SREBP2). The numbers indicate the sites of functional classes of LDL receptor gene mutations.

LDLRAP1 LDL receptor adaptor protein 1

Full size image

Numerous mutations (more than 1100) at the LDL receptor locus have been described as the cause of FH (http://www.ucl.ac.uk/fh). Interindividual phenotypic variation among patients with HeFH and HoFH is at least partially explained by LDL receptor activity and their causal mutations. The LDL receptor gene contains 18 exons and 17 introns and encodes 860 amino acids (Fig. 5.5). Mutations in the LDL receptor gene can be divided into five different functional classes; Class 1 mutations (null alleles) result in LDL receptor synthesis alteration. These mutations include nonsense mutations with a premature stop codon occurring early in the protein, large rearrangements including many bases, and insertions or deletions causing frameshift. Class 2 mutations cause an alteration in receptor transport to the Golgi apparatus or to the plasma membrane (completely, Class 2A; partially, Class 2B). Class 3 mutations result in an alteration of binding to apoB-100 despite normal transport to the plasma membrane. Class 4 mutations result in an endocytosis alteration despite normal binding to LDL, and class 5 mutations cause an alteration in the recycle mechanism (Fig. 5.6). Class 1 and class 2A are usually associated with null or less than 2% LDL receptor activity in cultured fibroblasts (receptor negative), while other classes are associated with reduced LDL receptor activity (receptor defective). Although the LDL receptor activity of the present case was not determined in vitro, it can be speculated that her LDL receptor function was preserved because cholesterol-lowering medication, including statin , was partially effective.

ApoB-100 is the ligand for the LDL receptor, and initially a missense mutation in the LDL receptor-binding domain of apoB-100 (Arg3500Gln) was described, followed by another mutation in the same codon (Arg3500Trp), as a cause of familial defective apolipoprotein B-100 (FDB) or FH2 (Soria et al. 1989). Both mutations are thought to reduce binding activity with the LDL receptor; eventually LDL particles in circulation are not cleared by the receptor. There is a clear localization of FDB; the frequency in Western countries is 1 in 1000 in the general population, and no cases of FDB have been reported in Japan so far (Nohara et al. 1995). Although clinical manifestations of FDB are usually milder than those of FH with the LDL receptor gene mutation (FH1), it is impossible to clinically distinguish FDB from FH1 without genetic analysis .

The proprotein convertase subtilisin/kexin type 9 (PCSK9) is the 9th member of the proprotein convertase family, which was the third cause of FH (Abifadel et al. 2003). After PCSK9 is synthesized as pre-pro PCSK9 in the ER, signal peptide (aa 1-30) is cleaved, followed by cleavage of the pro-domain (aa 31-152) by its own enzymatic activity. The pro-domain non-covalently binds to mature PCSK9 (aa 153-692) at the catalytic subunit, thereafter losing its enzymatic activity; this mature form is then secreted into circulation (Fig. 5.6). The pro-segment-PCSK9 complex binds to the EGF domain of the LDL receptor, and PCSK9 enters into cells via clathrin-coated vesicles as a chaperon with the receptor. In the acidic environment of endosomes, PCSK9 tightly binds to the LDL receptor, and PCSK9-LDL receptor complex is escorted to lysosomes for degradation (Fig. 5.6). PCSK9 regulates plasma LDL-C levels posttranscriptionally; thus, gain-of-function mutations in the PCSK9 gene result in FH (FH3). The LDL-C levels of patients with gain-of-function mutations in PCSK9 are widely distributed (Hopkins et al. 2015); thus, clinical distinguishing FH1 from FH3 is also difficult without measuring PCSK9 activity or genetic analysis . If PCSK9 is absent or inactivated, the LDL receptor effectively returns to the cell surface for recycling, eventually causing hypocholesterolemia.

Interestingly, the LDL receptor and PCSK9 are regulated by the same transcriptional factor, sterol regulatory element-binding protein 2 (SREBP2). SREBPs are inactive proteins bound to the ER. In the ER, SREBP binds to the SREBP cleavage-activating protein (SCAP), which is a sensor of intracellular sterols. When cellular cholesterol content is low, the SCAP-SREBP complex is able to move to the Golgi apparatus, where SREBP is sequentially cleaved by two proteases, S1P and S2P, and the NH2 terminal of SREBP is released to the cytoplasm. SREBP then translocates to the nucleus, where it activates transcription by binding to SRE-1 in the promoter regions of many genes encoding proteins involved in the homeostasis of cholesterol and other lipids. Statin , which is an inhibitor of cholesterol biosynthesis, upregulates SREBP2, increases the transcriptions of LDL receptors, and then increases PCSK9, which degrades LDL receptors. In contrast, when the cellular cholesterol content is in excess, SCAP undergoes conformational changes, which inhibits the transport of the SCAP-SREBP complex to the Golgi apparatus. As a result, the NH2 terminal of SREBP is not cleaved, and SREBP does not translocate to the nucleus to activate the target genes.

ARH is a recessive form of hypercholesterolemia. Fibroblasts from a patient with ARH have normal LDL receptor activity. The cholesterol turnover after LDL-apheresis using a rebound curve results in a defect in the degradation of cholesterol in ARH (Harada-Shiba et al. 1992). Subsequently, the cause of ARH was revealed as a deficiency in the adopter protein of the LDL receptor (LDL receptor adaptor protein 1), which is important for the internalization of the LDL receptor. Thus, the phenotype of ARH resembles HoFH with Class 5 mutations (Tada et al. 2015a). No family history of hypercholesterolemia suggesting FH is clinically important to distinguish ARH from HoFH.

Sitosterol is a type of plant sterol, which enters an enterocyte via the Niemann-Pick C1-like 1 (NPC1L1) protein together with cholesterol, and is excreted from the adenosine triphosphate-binding cassette sub-family G member 5/sub-family G member 8 (ABCG5/G8) (Fig. 5.3). Sitosterolemia is a rare autosomal recessive hyperlipidemia caused by dysfunctional mutations in ABCG5 or ABCG8. Sitosterolemia can exhibit severe hypercholesterolemia as well as tendon and skin xanthoma , resembling HoFH. In particular, infantile sitosterolemic patients with severe hypercholesterolemia sometimes exhibit systemic intertriginous xanthomas, which diminish quickly when weaned from breastfeeding (Tada et al. 2015c). Detecting hypersitosterolemia and determining the absence of family history of severe hypercholesterolemia are important to distinguish sitosterolemia from HoFH.

It is known that double heterozygous FH, which has two different mutations in FH-causing genes (i.e., LDL receptor and apoB or PCSK9) , resembles HoFH but with somewhat milder clinical manifestations .

5 Therapy

The primary goal for HeFH, and even for HoFH, is to have the same life expectancy and the same frequency of cardiovascular events as normal subjects. Most of hyperlipidemia other than FH develops after the second decade of life; thus, cumulative LDL-C from the birth is higher in FH than in other hyperlipidemia, even when the LDL-C levels after adulthood were the same. Therefore, intense LDL-C-lowering therapy for FH from an adequate age is crucial. A diet rich in saturated fat and cholesterol is associated with an increased flux of fats and cholesterol from the intestine. An increased cellular cholesterol content results in the downregulation of hepatic LDL receptor expression. Therefore, diet therapy consists of an adequate amount of total calories and restriction of carbohydrate, saturated fat, and cholesterol; maintaining adequate body weight is essential.

Although diet therapy is important, it is insufficient in reducing LDL-C levels in patients with FH to adequate levels. Thus, all FH patients ultimately become candidates for medical LDL-C-lowering therapy; most LDL-C-lowering medication upregulates LDL receptor activity by reducing the intracellular cholesterol content. HeFH patients, whereby half of the LDL receptors are intact, can usually be treated with ordinal cholesterol-lowering medication to acceptable levels. On the other hand, HoFH patients, who mostly lack the LDL receptor, are highly resistant to standard medical cholesterol-lowering therapy.

Statins inhibit 5-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate limiting enzyme of cholesterol biosynthesis in the mevalonate pathway, and reduce plasma LDL-C levels by increasing hepatic expression of LDL receptors. Statin is the most widely used LDL-C-lowering medication and is proved to reduce not only cardiovascular events but also all-cause mortality of patients at high risk of cardiovascular events. Moreover, the reduction rate of cardiovascular events and achieved LDL-C levels from several randomized-controlled studies using statin were linearly and significantly associated. Ezetimibe is the inhibitor of NPC1L1, the transmembrane protein that plays a key role in the cholesterol absorption by facilitating its uptake via vesicular endocytosis. Thus, ezetimibe also reduces the cholesterol content in hepatocytes and increase hepatic expression of LDL receptors. Ezetimibe combined with simvastatin therapy significantly reduced cardiovascular events in patients with acute coronary syndrome (Cannon et al. 2015). Bile acid sequestrants (resins) interrupt the enterohepatic circulation of bile acids, resulting in hepatic upregulation of LDL receptors. Combination of these three drugs , all of which increases hepatic LDL receptors, could decrease LDL-C levels to one third of pretreatment levels in patients with HeFH (Kawashiri et al. 2012).

PCSK9 regulates plasma LDL-C levels by directing hepatic cell surface LDL receptors to lysosomal degradation, resulting in an accumulation of LDLs in circulation because of reduced clearance. Evolocumab and alirocumab are fully human monoclonal antibody against human PCSK9, which can robustly reduce plasma LDL-C levels by more than 50% with monotherapy, and can be effectively combined with the other cholesterol-lowering drugs , such as statins and ezetimibe. Evolocumab combined with statin therapy significantly reduced cardiovascular events and ischemic strokes in patients with atherosclerotic cardiovascular diseases compared with statin therapy alone (Sabatine et al. 2017).

Microsomal triglyceride transfer protein (MTP) is a key protein in the assembly and secretion of apoB-containing lipoproteins in the liver (VLDL) and intestine (chylomicron) (Fig. 5.3). Lomitapide, a small molecule that inhibits MTP, does not require LDL receptor to decrease apoB-containing lipoproteins; thus, it is approved in several countries as an orphan drug for HoFH. While lomitapide decreases plasma LDL-C levels by 50% in HoFH, special attention should be paid for hepatic steatosis (Cuchel et al. 2013). Mipomersen is an antisense oligonucleotide , which is a small strand of nucleic acid that binds to messenger RNA to inhibit translation, for apoB. It also does not require the LDL receptor to decrease apoB-containing lipoproteins in HoFH (Raal et al. 2010). LDL-apheresis is a procedure that removes all apoB-containing lipoproteins (VLDL, IDL, LDL, and Lp(a)), the surface of which are exceptionally charged positive, using negatively charged dextran sulfate. Although LDL-apheresis is safe and does not remove HDL nor other negatively charged proteins with the exception of apoB-containing lipoproteins, it should be repeated weekly or biweekly because of rapid reaccumulation of LDL. Furthermore, it is an invasive and time-consuming procedure only available at specialized medical centers. Liver transplantation is an alternative therapy for HoFH and effectively reduces LDL-C; however, it is highly invasive and lifelong immunosuppressive therapy is required.

Under these conditions, innovative therapies are needed for HoFH. Among future treatment options, regenerative medicine using induced pluripotent stem (iPS) cells, which can introduce auto-hepatocyte with functional LDL receptors, is a theoretically attractive approach. Liver-directed gene therapy is another attractive option, but long-term stable expression of de novo gene by the host is difficult because of its immunologic exclusion. Antisense oligonucleotide therapy is also of interest for rare inherited disorders such as HoFH; antisense oligonucleotides against Lp(a) and PCSK9 are currently under development .

End-of-Chapter Questions

  1. 1.

    FH is thought to be the most frequent monogenic hereditary disorder. Why do you think FH is so frequent worldwide?

  2. 2.

    Why is tendon xanthoma very specific for FH? Why does hyperlipidemia other than FH not induce the development of tendon xanthoma even when the plasma LDL-C levels are the same with those of FH after adulthood?

  3. 3.

    What are the molecular causes of FH? What are the clinical characteristics and lipid levels of both HeFH and HoFH? Please explain what the compound heterozygous FH or double heterozygous FH.

  4. 4.

    What is the mechanism of statins, ezetimibe, and PCSK9 inhibitors to reduce LDL-C? What are the specific and novel therapies for HoFH and how do they reduce LDL-C?

Additional Materials

  • Which of the following lipoproteins are not associated with apolipoprotein B-100?

  1. 1.

    Chylomicron

  2. 2.

    VLDL

  3. 3.

    LDL

  4. 4.

    Lp(a)

  • Answer 1

  • Which of the following combinations between lipoproteins and their role is correct?

  1. 1.

    Chylomicron & Endogenous cholesterol carrier

  2. 2.

    VLDL & Provider of free fatty acids

  3. 3.

    LDL & Reverse cholesterol transporter

  4. 4.

    HDL & Exogenous cholesterol carrier

  • Answer 2

  • Which of the following physical findings is specific for FH?

  1. 1.

    Achilles tendon xanthoma

  2. 2.

    Arcus cornealis

  3. 3.

    Eruptive xanthoma on the skin

  4. 4.

    Xanthelasma on eyelids

  • Answer 1

  • Which of the following disorders are not be seen more frequently in FH than in normal subjects?

  1. 1.

    Abdominal aortic aneurysm

  2. 2.

    Cerebral infarction

  3. 3.

    Myocardial infarction

  4. 4.

    Peripheral artery disease

  • Answer 2

  • Which of the following combinations between drug and target molecule is not correct?

  1. 1.

    Evolocumab & PCSK9

  2. 2.

    Ezetimibe & NPC1L1

  3. 3.

    Lomitapide & apolipoprotein B-100

  4. 4.

    Statins & HMG-CoA reductase

  • Answer 3